title: Coordinated improvement in glucose tolerance, liver steatosis and obesity-associated inflammation by cannabinoid 1 receptor antagonism in fat Aussie mice.
abstract: OBJECTIVE
  Fat Aussie mice (foz/foz) are morbidly obese, glucose intolerant and have liver steatosis that develops into steatohepatitis on a high-fat diet. The cannabinoid 1 receptor (CB1) antagonist SR141716 has been shown to improve obesity-associated metabolic complications in humans and rodent models. The aim of this study was to assess the effect of SR141716 in foz/foz mice.
  
  
  METHODS
  Male wildtype (WT) and foz/foz mice were fed a chow or high-fat diet (45% saturated fat). Vehicle or SR141716 (10 mg kg(-1) per day) was administered in jelly once daily for 4 weeks from 4 months of age.
  
  
  RESULTS
  Foz/foz mice were obese but had less epididymal adipose tissue mass than fat-fed WT mice despite being significantly heavier. Liver weight was increased by twofold in foz/foz compared with WT mice and showed significant steatogenesis associated with impaired liver function. Foz/foz and fat-fed WT mice were glucose intolerant as determined by oral glucose tolerance test. In chow-fed foz/foz mice, SR141716 reduced body weight, liver weight, reversed hepatosteatosis and glucose intolerance. Subcutaneous white adipose tissue gene expression of the macrophage-specific marker Cd68 reflected the improvements in the metabolic status by SR141716 in these mice.
  
  
  CONCLUSIONS
  The results are consistent with the hypothesis that foz/foz mice have defective lipid metabolism, are unable to adequately store fat in adipose tissue but instead sequester fat ectopically in other metabolic tissues (liver) leading to insulin resistance and hepatic steatosis associated with inflammation. Our findings suggest that SR141716 can improve liver lipid metabolism in foz/foz mice in line with improved insulin sensitivity and adipose tissue inflammation.
authors.affiliation: School of Molecular Bioscience, University of Sydney, Sydney, New South Wales, Australia. kim.bellanderson@sydney.edu.au
authors.forename: K S
authors.initials: KS
authors.lastname: Bell-Anderson
authors.forename: L
authors.initials: L
authors.lastname: Aouad
authors.forename: H
authors.initials: H
authors.lastname: Williams
authors.forename: F R
authors.initials: FR
authors.lastname: Sanz
authors.forename: J
authors.initials: J
authors.lastname: Phuyal
authors.forename: C Z
authors.initials: CZ
authors.lastname: Larter
authors.forename: G C
authors.initials: GC
authors.lastname: Farrell
authors.forename: I D
authors.initials: ID
authors.lastname: Caterson
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018149:Glucose Intolerance / Q000378:metabolism; D005951:Glucose Tolerance Test; D007249:Inflammation / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D009767:Obesity, Morbid / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D000077285:Rimonabant
chemical_list: D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D000077285:Rimonabant